The impact of immunoglobulin in acute HIV infection on the HIV reservoir: a randomized controlled trial.
Antiretroviral therapy (ART) during acute HIV infection (AHI) restricts the HIV reservoir, but additional interventions are necessary to induce a cure. Intravenous immunoglobulin (IVIG) is not HIV-specific but is safe and temporarily reduces the HIV reservoir in chronic HIV infection. We present a randomized controlled trial to investigate whether IVIG plus ART in AHI reduces the HIV reservoir and immune activation compared with ART alone. Ten men with AHI (Fiebig II-IV) initiated ART (tenofovir, entricitabine, ritonavir boosted darunavir and raltegravir) at HIV-1 diagnosis and were randomized to ART alone or ART plus 5 days of IVIG, once virally suppressed (week 19). Blood samples were evaluated for viral reservoir, immune activation, immune exhaustion and microbial translocation. Flexible sigmoidoscopy was performed at weeks 19, 24 and 48, and gut proviral DNA and cell numbers determined. IVIG was well tolerated and no viral blips (> 50 HIV-1 RNA copies/mL) occurred during IVIG therapy. From baseline to week 48, total HIV DNA in peripheral blood mononuclear cells (PBMCs) (cases: -3.7 log10 copies/106 CD4 cells; controls: -3.87 log10 copies/106 CD4 cells) declined with no differences observed between the groups (P = 0.49). Declines were observed in both groups from week 19 to week 48 in total HIV DNA in PBMCs (P = 0.38), serum low copy RNA (P = 0.57) and gut total HIV DNA (P = 0.55), but again there were no significant differences between arms. Biomarkers of immune activation, immune exhaustion and microbial translocation and the CD4:CD8 ratio were similar between arms for all comparisons. Although safe, IVIG in AHI did not impact total HIV DNA, immune function or microbial translocation in peripheral blood or gut tissue.


Recent advances in sleep research.
The past two decades have witnessed substantial progress in methodology and knowledge in sleep research all over the world. The paper at hand will present some recent local contributions to this field. The first is a European project (SIESTA) focusing on the creation of an automatic sleep classification system and a normative database, including polysomnographic (PSG) and psychometric measures, in order to make it possible to diagnose sleep-disordered patients as compared with and age- and sex-matched healthy controls between 20 and 95 years of age. Subsequently, two trials on nonorganic sleep disorders in generalized anxiety disorder (GAD) and bruxism, as well as two trials on organic sleep disorders, i.e. snoring/sleep-disordered breathing treated with a mandibular advancement device (I.S.T.) and restless legs syndrome treated with ropinirole and gabapentin, will be discussed.


Intestinal invasive amebiasis: an experimental model in rodents using axenic or monoxenic strains of Entamoeba histolytica.
A new experimental model for the production of early stages of invasive intestinal amebiasis in hamsters or guinea pigs with axenic or monoxenic cultures of Entamoeba histolytica of the HM1:IMSS strain is reported. The model is called the washed-closed cecal loop, because it involves the washing out of the cecum contents of conventionally raised animals and the formation of a closed loop, into which amebas are inoculated. Colonization occurred in all inoculated animals. After 48 hr, macroscopic ulcerations of the cecal mucosa were found in approximately one-half (5/12) of the animals inoculated with axenic amebas and in more than two-thirds (10/12) of those inoculated with monoxenic parasites. The amebic nature of the mucosal ulcerations was confirmed by light and transmission electron microscopy, as well as by scanning electron microscopy (SEM) of fractured samples of cecal mucosa. SEM provided a rapid and reliable technique to assess both the extent and the nature of the lesions. This model is particularly useful for the study of the pathogenesis of early intestinal lesions produced by virulent amebas, and may also be applied to experimental studies on the immunology of invasive intestinal amebiasis.


Climate and plant community diversity in space and time.
Climate strongly shapes plant diversity over large spatial scales, with relatively warm and wet (benign, productive) regions supporting greater numbers of species. Unresolved aspects of this relationship include what causes it, whether it permeates to community diversity at smaller spatial scales, whether it is accompanied by patterns in functional and phylogenetic diversity as some hypotheses predict, and whether it is paralleled by climate-driven changes in diversity over time. Here, studies of Californian plants are reviewed and new analyses are conducted to synthesize climate-diversity relationships in space and time. Across spatial scales and organizational levels, plant diversity is maximized in more productive (wetter) climates, and these consistent spatial relationships are mirrored in losses of taxonomic, functional, and phylogenetic diversity over time during a recent climatic drying trend. These results support the tolerance and climatic niche conservatism hypotheses for climate-diversity relationships, and suggest there is some predictability to future changes in diversity in water-limited climates.


Clinical implementation of an exit detector-based dose reconstruction tool for helical tomotherapy delivery quality assurance.
The aim of this study was to validate the accuracy of an exit detector-based dose reconstruction tool for helical tomotherapy (HT) delivery quality assurance (DQA). Exit detector-based DQA tool was developed for patient-specific HT treatment verification. The tool performs a dose reconstruction on the planning image using the sinogram measured by the HT exit detector with no objects in the beam (i.e., static couch), and compares the reconstructed dose to the planned dose. Vendor supplied (three "TomoPhant") plans with a cylindrical solid water ("cheese") phantom were used for validation. Each "TomoPhant" plan was modified with intentional multileaf collimator leaf open time (MLC LOT) errors to assess the sensitivity and robustness of this tool. Four scenarios were tested; leaf 32 was "stuck open," leaf 42 was "stuck open," random leaf LOT was closed first by mean values of 2% and then 4%. A static couch DQA procedure was then run five times (once with the unmodified sinogram and four times with modified sinograms) for each of the three "TomoPhant" treatment plans. First, the original optimized delivery plan was compared with the original machine agnostic delivery plan, then the original optimized plans with a known modification applied (intentional MLC LOT error) were compared to the corresponding error plan exit detector measurements. An absolute dose comparison between calculated and ion chamber (A1SL, Standard Imaging, Inc., WI, USA) measured dose was performed for the unmodified "TomoPhant" plans. A 3D gamma evaluation (2%/2 mm global) was performed by comparing the planned dose ("original planned dose" for unmodified plans and "adjusted planned dose" for each intentional error) to exit detector-reconstructed dose for all three "Tomophant" plans. Finally, DQA for 119 clinical (treatment length <25 cm) and three cranio-spinal irradiation (CSI) plans were measured with both the ArcCHECK phantom (Sun Nuclear Corp., Melbourne, FL, USA) and the exit detector DQA tool to assess the time required for DQA and similarity between two methods. The measured ion chamber dose agreed to within 1.5% of the reconstructed dose computed by the exit detector DQA tool on a cheese phantom for all unmodified "Tomophant" plans. Excellent agreement in gamma pass rate (>95%) was observed between the planned and reconstructed dose for all "Tomophant" plans considered using the tool. The gamma pass rate from 119 clinical plan DQA measurements was 94.9% ± 1.5% and 91.9% ± 4.37% for the exit detector DQA tool and ArcCHECK phantom measurements (P = 0.81), respectively. For the clinical plans (treatment length <25 cm), the average time required to perform DQA was 24.7 ± 3.5 and 39.5 ± 4.5 min using the exit detector QA tool and ArcCHECK phantom, respectively, whereas the average time required for the 3 CSI treatments was 35 ± 3.5 and 90 ± 5.2 min, respectively. The exit detector tool has been demonstrated to be faster for performing the DQA with equivalent sensitivity for detecting MLC LOT errors relative to a conventional phantom-based QA method. In addition, comprehensive MLC performance evaluation and features of reconstructed dose provide additional insight into understanding DQA failures and the clinical relevance of DQA results.


The development of estrogen and progestin radiopharmaceuticals for imaging breast cancer.
The presence of receptors for estrogens and progestins in many breast tumors provides a means for imaging these tumors using positron emission tomography (PET) with appropriate fluorine-18 labeled estrogen and progestin radiopharmaceuticals. In this context, the estrogen analog 16 alpha-[18F]fluoroestradiol (FES) has already proven to be an effective imaging agent for estrogen receptor-positive tumors. Clinical studies comparing FES images with those based on the metabolic probe 2-[18F]fluoro-2-deoxyglucose (FDG) in patients before and after tamoxifen hormone therapy are underway. Several fluorine-18 labeled progestins have been prepared, and efforts are underway to develop methods for labeling steroid receptor imaging agents with the widely available radionuclide technetium-99m, using both pendant and integrated approaches. Breast tumor imaging with FES and FDG shows an interesting relationship between tumor metabolic response (assessed with FDG) and tumor estrogen receptor levels (assessed with FES). The fluorine-18 labeled progestins show excellent target tissue selective distribution in experimental animals and are ready for imaging studies in humans. The development of steroids labeled with technetium-99m poses special challenges because of the metallic nature of this radioisotope.


Deformation-Induced Photoprogrammable Pattern of Polyurethane Elastomers Based on Poisson Effect.
Elastomers with high aspect ratio surface patterns are a promising class of materials for designing soft machines in the future. Here, a facile method for fabricating surface patterns on polyurethane elastomer by subtly utilizing the Poisson effect and gradient photocrosslinking is demonstrated. By applying uniaxial tensile strains, the aspect ratio of the surface patterns can be optionally manipulated. At prestretched state, the pattern on the polyurethane elastomer can be readily constructed through compressive stress, resulting from the gradient photocrosslinking via selective photodimerization of an anthracene-functionalized polyurethane elastomer (referred to as ANPU). The macromolecular aggregation structures during stretching deformation significantly contribute to the fabrication of high aspect ratio surface patterns. The insightful finite element analysis well demonstrates that the magnitude and distribution of internal stress in the ANPU elastomer can be regulated by selectively gradient crosslinking, leading to polymer chains migrate from the exposed region to the unexposed region, thereby generating a diverse array of surface patterns. Additionally, the periodic surface patterns exhibit tunable structural color according to the different stretching states and are fully reversible over multiple cycles, opening up avenues for diverse applications such as smart displays, stretchable strain sensors, and anticounterfeiting devices.


Integrator function in the oculomotor system is dependent on sensory context.
The oculomotor integrator is usually defined by the characteristics of decay in gaze after saccades to flashed targets or after spontaneous gaze shifts in the dark. This property is then presumed fixed and accessed by other ocular reflexes, such as the vestibuloocular reflex (VOR) or pursuit, to shape motoneural signals. An alternate view of this integrator proposes that it relies on a distributed network, which should change its properties with sensory-motor context. Here we demonstrate in 10 normal subjects that the function of integration can vary in an individual with the imposed test. The value of the time constant for the decay of gaze holding in the dark can be significantly different from the effective integration time constant estimated from VOR responses. Hence analytical tools for the study of dynamics in ocular reflexes must allow for nonideal and labile integrator function. The mechanisms underlying such labile integration remain to be explored and may be different in various ocular reflexes (e.g., visual versus vestibular).


Fracture fixation strategy and specific muscle tissue availability of neutrophilic granulocytes following mono- and polytrauma: intramedullary nailing vs. external fixation of femoral fractures.
In the stabilization of femoral fractures in mono- and polytrauma, clinical practice has shown better care through intramedullary nailing. However, the reason why this is the case is not fully understood. In addition to concomitant injuries, the immunological aspect is increasingly coming to the fore. Neutrophil granulocytes (PMNL), in particular next to other immunological cell types, seem to be associated with the fracture healing processes. For this reason, the early phase after fracture (up to 72 h after trauma) near the fracture zone in muscle tissue was investigated in a pig model. A mono- and polytrauma pig model (sole femur fracture or blunt thoracic trauma, hemorrhagic shock, liver laceration, and femur fracture) was used to demonstrate the immunological situation through muscle biopsies and their analysis by histology and qRT-PCR during a 72 h follow-up phase. Two stabilization methods were used (intramedullary nail vs. external fixator) and compared with a nontraumatized sham group. Monotrauma shows higher PMNL numbers in muscle tissue compared with polytrauma (15.52 ± 5.39 mono vs. 8.23 ± 3.36 poly; p = 0.013), regardless of the treatment strategy. In contrast, polytrauma shows a longer lasting invasion of PMNL (24 h vs. 72 h). At 24 h in the case of monotrauma, the fracture treated with external fixation shows more PMNL than the fracture treated with intramedullary nailing (p = 0.026). This difference cannot be determined in polytrauma probably caused by a generalized immune response. Both monotrauma and polytrauma show a delayed PMNL increase in the muscle tissue of the uninjured side. The use of intramedullary nailing in monotrauma resulted in a significant increase in IL-6 (2 h after trauma) and IL-8 (24 and 48 h after trauma) transcription. The reduction of PMNL invasion into the nearby muscle tissue of a monotrauma femur fracture stabilized by intramedullary nailing supports the advantages found in everyday clinical practice and therefore underlines the usage of nailing. For the polytrauma situation, the fixation seems to play a minor role, possibly due to a generalized immune reaction.


Spatial variability in seed predation in Primula farinosa: local population legacy versus patch selection.
Spatio-temporal variation in seed predation may strongly influence both plant population dynamics and selection on plant traits. The intensity of seed predation may depend on a number of factors, but the relative importance of previous predator abundance ("local legacy"), spatial distribution of the host plant, environmental factors and plant characteristics has been explored in few species. We monitored seed predation in the perennial herb Primula farinosa, which is dimorphic for scape length, during 5 consecutive years, in a 10-km x 4-km area comprising 79 P. farinosa populations. A transplant experiment showed that the seed predator, the oligophagous tortricid moth Falseuncaria ruficiliana, was not dispersal limited at the spatial scale corresponding to typical distances between P. farinosa populations. Correlations between population characteristics and incidence and intensity of seed predation varied among years. The incidence of the seed predator was positively correlated with host population size and mean number of flowers, while intensity of seed predation in occupied patches was positively related to the frequency of the long-scaped morph in 2 years and negatively related to host population size in 1 year. In both scape morphs, predation tended to increase with increasing frequency of the long morph. There was no evidence of a local legacy; incidence and intensity of seed predation were not related to the abundance of the seed predator in the population in the previous year. Taken together, the results indicate that among-population variation in seed predation intensity is determined largely by patch selection and that the seed predator's preference for tall and many-flowered inflorescences may not only affect selection on plant traits within host plant populations, but also the overall intensity of seed predation.


On the efficiency of the genetic code after frameshift mutations.
Statistical and biochemical studies of the standard genetic code (SGC) have found evidence that the impact of mistranslations is minimized in a way that erroneous codes are either synonymous or code for an amino acid with similar polarity as the originally coded amino acid. It could be quantified that the SGC is optimized to protect this specific chemical property as good as possible. In recent work, it has been speculated that the multilevel optimization of the genetic code stands in the wider context of overlapping codes. This work tries to follow the systematic approach on mistranslations and to extend those analyses to the general effect of frameshift mutations on the polarity conservation of amino acids. We generated one million random codes and compared their average polarity change over all triplets and the whole set of possible frameshift mutations. While the natural code-just as for the point mutations-appears to be competitively robust against frameshift mutations as well, we found that both optimizations appear to be independent of each other. For both, better codes can be found, but it becomes significantly more difficult to find candidates that optimize all of these features-just like the SGC does. We conclude that the SGC is not only very efficient in minimizing the consequences of mistranslations, but rather optimized in amino acid polarity conservation for all three effects of code alteration, namely translational errors, point and frameshift mutations. In other words, our result demonstrates that the SGC appears to be much more than just "one in a million".


Characterization of clinical isolates of Enterobacteriaceae from Italy by the BD Phoenix extended-spectrum beta-lactamase detection method.
Production of extended-spectrum beta-lactamases (ESBLs) is an important mechanism of beta-lactam resistance in Enterobacteriaceae: Identification of ESBLs based on phenotypic tests is the strategy most commonly used in clinical microbiology laboratories. The Phoenix ESBL test (BD Diagnostic Systems, Sparks, Md.) is a recently developed automated system for detection of ESBL-producing gram-negative bacteria. An algorithm based on phenotypic responses to a panel of cephalosporins (ceftazidime plus clavulanic acid, ceftazidime, cefotaxime plus clavulanic acid, cefpodoxime, and ceftriaxone plus clavulanic acid) was used to test 510 clinical isolates of Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Proteus mirabilis, Providencia stuartii, Morganella morganii, Enterobacter aerogenes, Enterobacter cloacae, Serratia marcescens, Citrobacter freundii, and Citrobacter koseri. Of these isolates, 319 were identified as ESBL producers, and the remaining 191 were identified as non-ESBL producers based on the results of current phenotypic tests. Combined use of isoelectric focusing, PCR, and/or DNA sequencing demonstrated that 288 isolates possessed bla(TEM-1)- and/or bla(SHV-1)-derived genes, and 28 had a bla(CTX-M) gene. Among the 191 non-ESBL-producing isolates, 77 isolates produced an AmpC-type enzyme, 110 isolates possessed TEM-1, TEM-2, or SHV-1 beta-lactamases, and the remaining four isolates (all K. oxytoca strains) hyperproduced K1 chromosomal beta-lactamase. The Phoenix ESBL test system gave positive results for all the 319 ESBL-producing isolates and also for two of the four K1-hyperproducing isolates of K. oxytoca. Compared with the phenotypic tests and molecular analyses, the Phoenix system displayed 100% sensitivity and 98.9% specificity. These findings suggest that the Phoenix ESBL test can be a rapid and reliable method for laboratory detection of ESBL resistance in gram-negative bacteria.


Predictors of responses to stress among families coping with poverty-related stress.
This study tested how poverty-related stress (PRS), psychological distress, and responses to stress predicted future effortful coping and involuntary stress responses one year later. In addition, we explored age, sex, ethnicity, and parental influences on responses to stress over time. Hierarchical linear modeling analyses conducted with 98 low-income families (300 family members: 136 adults, 82 school-aged children, 82 adolescents) revealed that primary control coping, secondary control coping, disengagement, involuntary engagement, and involuntary disengagement each significantly predicted future use of that response. Primary and secondary control coping also predicted less maladaptive future responses to stress, while involuntary responses to stress undermined the development of adaptive responding. Age, sex, and interactions among PRS and prior coping were also found to predict certain responses to stress. In addition, child subgroup analyses demonstrate the importance of parental modeling of coping and involuntary stress responses, and warmth/nurturance and monitoring practices. Results are discussed with regard to the implications for preventive interventions with families in poverty.


Simulation of the electrochemical behavior of multi-redox systems. Current potential studies on multiheme cytochromes.
The direct unmediated electrochemical response of the tetrahemic cytochrome c3 isolated from sulfate reducers Desulfovibrio baculatus (DSM 1743) and D. vulgaris (strain Hildenborough), was evaluated using different electrode systems [graphite (edge cut), gold, semiconductor (InO2) and mercury)] and different electrochemical methods (cyclic voltammetry and differential pulse voltammetry). A computer program was developed for the theoretical simulation of a complete cyclic voltammetry curve, based on the method proposed by Nicholson and Shain [Nicholson, R.S. & Shain, I. (1964) Anal. Chem. 36, 706-723], using the Gauss-Legendre method for calculation of the integral equations. The experimental data obtained for this multi-redox center protein was deconvoluted in to the four redox components using theoretically generated cyclic voltammetry curves and the four mid-point reduction potentials determined. The pH dependence of the four reduction potentials was evaluated using the deconvolution method described.


mTOR signaling is involved in indomethacin and nimesulide suppression of colorectal cancer cell growth via a COX-2 independent pathway.
Inhibition of mammalian target of rapamycin (mTOR) represents an attractive target for anticancer therapy, but its role in suppression of colorectal cancer (CRC) cell growth by cyclooxygenase-2 (COX-2) inhibitors is unclear. Here, we analyzed the effect of indomethacin (Indo, a nonselective COX-2 inhibitor) and nimesulide (Nim, a selective COX-2 inhibitor) on mTOR signaling in CRC cells in vitro and in vivo to determine the dependence of this effect on COX-2. Human CRC cell lines with varying COX-2 expression levels were treated with Indo and Nim. Western blot test was performed to detect mTOR-related components (mTOR, p70s6 K, and 4EBP1), and cell viability, cell cycle, and apoptosis were assessed. HCT116 and SW1116 cells were injected into athymic nude mice to establish a CRC xenograft model. After treatment with Nim, tumor volume, mTOR signaling, and apoptosis were evaluated in this model. HT29 and SW1116 cells were also treated with Nim after transfection with COX-2-specific small interfering RNA (siRNA) to assess dependence of COX-2 on mTOR signaling under drug treatment. Both Indo and Nim reduced mTOR signaling activity in CRC cells that differ in their COX-2 expression in vitro and in vivo. Additionally, Indo and Nim could reduce the mTOR signaling activity after COX-2 silencing in CRC cells. mTOR signaling is involved in Indo- and Nim-mediated suppression of CRC growth via a COX-2 independent pathway. This study unveils a novel mechanism through which COX-2 inhibitors exerts their anticancer effects and further emphasizes targeting mTOR signaling in anticancer therapy.


Assessment of learning in simulator-based arthroscopy training with the diagnostic arthroscopy skill score (DASS) and neurophysiological measures.
Virtual arthroscopic training has become increasingly popular. However, there is a lack of efficiency-based tracking of the trainee, which may be critical for determining the specifics of training programs and adapting them for the needs of each trainee. This study aims to evaluate and compare the measures obtained with a non-invasive neurophysiological method with The Diagnostic Arthroscopy Skill Score (DASS), a commonly used assessment tool for evaluating arthroscopic skills. The study collected simulator performance scores, consisting of "Triangulation Right Hand", "Triangulation Left Hand", "Catch the Stars" and "Three Rings" and DASS scores from 22 participants (11 novices, 11 experts). These scores were obtained while participants underwent a structured program of exercises for the fundamentals of arthroscopic surgery training (FAST) and knee module using a simulator-based arthroscopy device. During the evaluation, data on oxy-hemoglobin and deoxy-hemoglobin levels in the prefrontal cortex were collected using the Functional Near-Infrared Spectroscopy (fNIRS) imaging system. Performance scores, DASS scores, and fNIRS data were subsequently analyzed to determine any correlation between performance and cortex activity. The simulator performance scores and the DASSPart2 scores were significantly higher in the expert group compared to the novice group (200.1 ± 28.5 vs 172.5 ± 48.9, p = 0.04 and 9.4 ± 5.6 vs. 5.4 ± 5.6 p = 0.02). In the expert group, fNIRS data showed a significantly lower prefrontal cortex activation during fundamental tasks in the FAST module, indicating significantly more efficient mental resource use. The analysis of cognitive workload changes during simulation-based arthroscopy training revealed a significant correlation between the trainees' DASS scores and fNIRS data. This correlation suggests the potential use of fNIRS data and DASS scores as additional metrics to create adaptive training protocols for each participant. By incorporating these metrics, the training process can be optimized, leading to more efficient arthroscopic training and better preparedness for clinical operations. III.


Conservation and metaphor acquisition in hearing-impaired children. Some relationships with communication mode, hearing acuity, schooling, and age.
This study focused on conservation and metaphor acquisition in 35 hearing-impaired children who used different modes of communication and who spanned a wide age range. Children who used either cued speech or oral-aural communication modes were tested at two different school sites. Relationships were determined between the dependent variables, conservation and metaphor, and the independent variables of age, degree of hearing loss, years of schooling, and mode of communication. Findings revealed a significant positive relationship between conservation and metaphor in both communication modes. Significant relationships between age and metaphor and between age and conservation were also found, suggesting that experience plays an important role in understanding both of them. Neither conservation nor metaphor was significantly related to either degree of hearing loss or communication mode. The conservation order of acquisition was number (91%), weight (60%), volume (50%), and liquid (46%). Suggestions for teachers based on the findings are presented.


Dopamine, Norepinephrine and Serotonin Participate Differently in Methylphenidate Action in Concomitant Behavioral and Ventral Tegmental Area, Locus Coeruleus and Dorsal Raphe Neuronal Study in Young Rats.
Methylphenidate (MPD), known as Ritalin, is a psychostimulant used to treat children, adults, and the elderly. MPD exerts its effects through increasing concentrations of dopamine (DA), norepinephrine (NE), and serotonin (5-HT) in the synaptic cleft. Concomitant behavioral and neuronal recording from the ventral tegmental area (VTA), locus coeruleus (LC), and from the dorsal raphe (DR) nucleus, which are the sources of DA, NE, and 5-HT to the mesocorticolimbic circuit, were investigated following acute and repetitive (chronic) saline, 0.6, 2.5, or 10.0 mg/kg MPD. Animals received daily saline or MPD administration on experimental days 1 to 6 (ED1-6), followed by a 3-day washout period and MPD rechallenge on ED10. Each chronic MPD dose elicits behavioral sensitization in some animals while inducing behavioral tolerance in others. The uniqueness of this study is in the evaluation of neuronal activity based on the behavioral response to chronic MPD. Neuronal excitation was observed mainly in brain areas of animals exhibiting behavioral sensitization, while neuronal attenuation following chronic MPD was observed in animals expressing behavioral tolerance. Different ratios of excitatory/inhibitory neuronal responses were obtained from the VTA, LC, or DR following chronic MPD. Thus, each brain area responds differently to each MPD dose used, suggesting that DA, NE, and 5-HT in the VTA, LC, and DR exert different effects.


Phase locking and in-phase supermode selection in monolithic multicore fiber lasers.
We report a compact multicore fiber laser that utilizes an all-fiber approach for phase locking and in-phase supermode selection. By splicing passive coreless fibers of controlled lengths to both ends of an active 19-core fiber, we demonstrate that the fundamental in-phase supermode can be selectively excited with a completely monolithic fiber device, instead of conventional free-space and bulk optics, to achieve phase-locked operation for a multiemitter laser device.


Nucleotide sequence of the 3'-terminal two-thirds of the grapevine leafroll-associated virus-3 genome reveals a typical monopartite closterovirus.
The RNA genome of grapevine leafroll-associated closterovirus-3 (GLRaV-3) was cloned as a cDNA generated from GLRaV-3-specific dsRNA, and a partial genome sequence of 13154 nucleotides (nt) including the 3' terminus was determined. The sequenced portion contained 13 open reading frames (ORFs) potentially encoding, in the 5'-3' direction, proteins of > 77 kDa (ORF1a; helicase, HEL), 61 kDa (ORF1b; RNA-dependent RNA polymerase, RdRp), 6 kDa (ORF2), 5 kDa (ORF3, small transmembrane protein), 59 kDa (ORF4; heat shock protein 70, HSP70), 55 kDa (ORF5), 35 kDa (ORF6; coat protein, CP), 53 kDa (ORF7; diverged coat protein, CPd), 21 kDa (ORF8), 20 kDa (ORF9), 20 kDa (ORF10), 4 kDa (ORF11), 7 kDa (ORF12), and an untranslated region of 277 nt. ORF1b is probably expressed via a +1 ribosomal frameshift mechanism, most similar to that of lettuce infectious yellows virus (LIYV). Phylogenetic analysis using various gene sequences (HEL, RdRp, HSP70 and CP) clearly demonstrated that GLRaV-3, a mealybug-transmissible closterovirus, is positioned independently from aphid-transmissible monopartite closteroviruses (beet yellows, citrus tristeza and beet yellows stunt) and whitefly-transmissible bipartite closterovirus (lettuce infectious yellows, LIYV). However, another alleged mealybug-transmissible closterovirus, little cherry virus, was shown to be more closely related to the whitefly-transmissible LIYV than to GLRaV-3.


System-level network simulation for robust centrifugal-microfluidic lab-on-a-chip systems.
Centrifugal microfluidics shows a clear trend towards a higher degree of integration and parallelization. This trend leads to an increase in the number and density of integrated microfluidic unit operations. The fact that all unit operations are processed by the same common spin protocol turns higher integration into higher complexity. To allow for efficient development anyhow, we introduce advanced lumped models for network simulations in centrifugal microfluidics. These models consider the interplay of centrifugal and Euler pressures, viscous dissipation, capillary pressures and pneumatic pressures. The simulations are fast and simple to set up and allow for the precise prediction of flow rates as well as switching and valving events. During development, channel and chamber geometry variations due to manufacturing tolerances can be taken into account as well as pipetting errors, variations of contact angles, compliant chamber walls and temperature variations in the processing device. As an example of considering these parameters during development, we demonstrate simulation based robustness analysis for pneumatic siphon valving in centrifugal microfluidics. Subsequently, the influence of liquid properties on pumping and valving is studied for four liquids relevant for biochemical analysis, namely, water (large surface tension), blood plasma (large contact angle hysteresis), ethanol/water (highly wetting) and glycerine/water (highly viscous). In a second example, we derive a spin protocol to attain a constant flow rate under varying pressure conditions. Both examples show excellent agreement with experimental validations.


NMR analysis of lignins in CAD-deficient plants. Part 1. Incorporation of hydroxycinnamaldehydes and hydroxybenzaldehydes into lignins.
Peroxidase/H2O2-mediated radical coupling of 4-hydroxycinnamaldehydes produces 8-O-4-, 8-5-, and 8-8-coupled dehydrodimers as has been documented earlier, as well as the 5-5-coupled dehydrodimer. The 8-5-dehydrodimer is however produced kinetically in its cyclic phenylcoumaran form at neutral pH. Synthetic polymers produced from mixtures of hydroxycinnamaldehydes and normal monolignols provide the next level of complexity. Spectral data from dimers, oligomers, and synthetic polymers have allowed a more substantive assignment of aldehyde components in lignins isolated from a CAD-deficient pine mutant and an antisense-CAD-downregulated transgenic tobacco. CAD-deficient pine lignin shows enhanced levels of the typical benzaldehyde and cinnamaldehyde end-groups, along with evidence for two types of 8-O-4-coupled coniferaldehyde units. The CAD-downregulated tobacco also has higher levels of hydroxycinnamaldehyde and hydroxybenzaldehyde (mainly syringaldehyde) incorporation, but the analogous two types of 8-O-4-coupled products are the dominant features. 8-8-Coupled units are also clearly evident. There is clear evidence for coupling of hydroxycinnamaldehydes to each other and then incorporation into the lignin, as well as for the incorporation of hydroxycinnamaldehyde monomers into the growing lignin polymer. Coniferaldehyde and sinapaldehyde (as well as vanillin and syringaldehyde) co-polymerize with the traditional monolignols into lignins and do so at enhanced levels when CAD-deficiency has an impact on the normal monolignol production. The implication is that, particularly in angiosperms, the aldehydes behave like the traditional monolignols and should probably be regarded as authentic lignin monomers in normal and CAD-deficient plants.


Density and localization of calcium channels of the L-type in human pulmonary artery.
The pharmacological profile and the anatomical localization of Ca2+ channels of the L-type were investigated in the human pulmonary artery to identify possible mechanisms involved in the regulation of the pulmonary vascular tone. Analysis was performed on slide-mounted frozen sections of human pulmonary artery using radioligand binding assay techniques associated with light microscope autoradiography. [3H]-Nicardipine was used as ligand. Human renal and right coronary arteries also were used as systemic reference arteries. Binding of [3H]-nicardipine to sections of human pulmonary artery was time-, temperature- and concentration-dependent, saturable and reversible. In the human pulmonary artery, the apparent equilibrium dissociation constant (Kd) was 0.12+/-0.02 nM and the maximum density of binding sites (Bmax) was 38.15+/-2.25 fmol/mg tissue. Kd values were 0.3+/-0.01 nM and 0.5+/-0.02 in the human renal artery and right coronary artery respectively. Bmax values were 248+/-16 fmol/mg tissue and 173+/-9.5 fmol/mg tissue in the human renal artery and right coronary artery respectively. The pharmacological profile of [3H]-nicardipine binding to sections of human pulmonary artery was consistent with the labeling of Ca2+ channels of the L-type. It was similar in the pulmonary artery and in the human renal and right coronary arteries. Light microscope autoradiography revealed a high density of [3H]-nicardipine binding sites within smooth muscle of the tunica media of human pulmonary artery as well as of human renal and right coronary arteries. A lower accumulation of the radioligand occurred in the tunica adventitia. No specific binding was noticeable in the tunica intima. Our data suggest that human pulmonary artery expresses Ca2+ channels of the L-type sensitive to dihydropyridines. These sites have similar affinity and lower density than those expressed by systemic arteries. The presence of Ca2+ channels of the L-type in human pulmonary artery suggests that their pharmacological manipulation may be considered in the treatment of pulmonary hypertension.


Impact of oxidative/nitrosative stress and inflammation on cognitive functions in patients with recurrent depressive disorders.
Data show that up to 38.2% of the European population have a mental disorder and that recurrent depressive disorder (rDD) is among the most commonly diagnosed disabling diseases. Over the last few years, neurocognitive impairments in rDD have become a new research front focusing on the role of cognitive decline during the course of rDD and in relation to its clinical presentation and prognosis. Both immune-inflammatory and oxidative and nitrosative stress (O&NS) processes potentially play a role in development of cognitive dysfunction in rDD. New evidence shows that chronic inflammatory and O&NS reactions occur in the brains of patients with neurodegenerative disorders and those with rDD. This narrative review presents the current state of knowledge on the possible impact of selected inflammatory and O&NS enzymes on cognitive functioning in patients with rDD. We focus on manganese superoxide dismutase (MnSOD), inducible nitric oxide synthase (iNOS), and myeloperoxidase (MPO).


Simultaneous Inhibition of Conduction Loss and Enhancement of Polarization Intensity of Polyetherimide Dielectrics for High-Temperature Capacitive Energy Storage.
Polymer dielectrics with excellent high-temperature capacitive energy storage performance are in urgent demand for modern power electronic devices and high-voltage electrical systems. Nevertheless, the energy storage capability usually degrades dramatically at increased temperatures, owing to the exponentially increased conduction loss. Herein, a trace of commercially available aluminum nitride (AlN) nanoparticles is incorporated into the poly(ether imide) (PEI) matrix to inhibit the conduction loss. The nanostructured AlN component with a large specific surface area can provide abundant sites for the collision of carriers. More importantly, the generated new trap energy levels can immobilize the carriers, accordingly contributing to the reduction in leakage current. From this, the discharged energy density at 150 °C of PEI composites increases by 82.13% from 2.63 J/cm3 for pristine PEI to 4.79 J/cm3 for PEI composites. This work establishes a facile approach to enhancing the high-temperature capacitive performance of polymer dielectrics.


Type 2 Diabetes Mellitus is Associated with the Immunoglobulin G N-Glycome through Putative Proinflammatory Mechanisms in an Australian Population.
Type 2 diabetes mellitus (T2DM) is a common complex trait arising from interactions among multiple environmental, genomic, and postgenomic factors. We report here the first attempt to investigate the association between immunoglobulin G (IgG) N-glycan patterns, T2DM, and their clinical risk factors in an Australian population. N-glycosylation of proteins is one of the most frequently observed co- and post-translational modifications, reflecting, importantly, the real-time status of the interplay between the genomic and postgenomic factors. In a community-based case-control study, 849 participants (217 cases and 632 controls) were recruited from an urban community in Busselton, Western Australia. We applied the ultraperformance liquid chromatography method to analyze the composition of IgG N-glycans. We then conducted Spearman's correlation analyses to explore the association between glycan biomarker candidates and clinical risk factors. We performed area under the curve (AUC) analysis of the receiver operating characteristic curves by fivefold cross-validation for clinical risk factors, IgG glycans, and their combination. Two directly measured and four derived glycan peaks were significantly associated with T2DM, after correction for extensive clinical confounders and false discovery rate, thus suggesting that IgG N-glycan traits are highly correlated with T2DM clinical risk factors. Moreover, adding the IgG glycan profiles to fasting blood glucose in the logistic regression model increased the AUC from 0.799 to 0.859. The AUC for IgG glycans alone was 0.623 with a 95% confidence interval 0.580-0.666. In addition, our study provided new evidence of diversity in T2DM complex trait by IgG N-glycan stratification. Six IgG glycan traits were firmly associated with T2DM, which reflects an increased proinflammatory and biological aging status. In summary, our study reports novel associations between the IgG N-glycome and T2DM in an Australian population and the putative role of proinflammatory mechanisms. Furthermore, IgG N-glycomic alterations offer future prospects as inflammatory biomarker candidates for T2DM diagnosis, and monitoring of T2DM progression to cardiovascular disease or renal failure.


Two invertebrate acetylcholinesterases show activation followed by inhibition with substrate concentration.
In vertebrates there are two cholinesterases, with differences in catalytic behaviour with respect to substrate concentration: butyrylcholinesterase displays an increased activity at low substrate concentrations, whereas acetylcholinesterase displays inhibition by excess substrate. In two invertebrates, Drosophila melanogaster and Caenorhabditis elegans, we found cholinesterases that showed both kinetic complexities: substrate activation at low substrate concentrations followed by inhibition at higher concentrations. These triphasic kinetics can be explained by the presence of two enzymes with different kinetic behaviours or more probably by the existence of a single enzyme regulated by the substrate concentration.


Examining inequities in incidence of catastrophic health expenditures on different healthcare services and health facilities in Nigeria.
There is limited evidence about levels of socio-economic and other differences in catastrophic health spending in Nigeria and in many sub-Saharan African countries. The study estimated the level of catastrophic healthcare expenditures for different healthcare services and facilities and their distribution across socioeconomic status (SES) groups. The study took place in four Local Government Areas in southeast Nigeria. Data were collected using interviewer-administered questionnaires administered to 4873 households. Catastrophic health expenditures (CHE) were measured using a threshold of 40% of monthly non-food expenditure. We examined both total monthly health expenditure and disaggregated expenditure by source and type of care. The average total household health expenditure per month was 2354 Naira ($19.6). For outpatient services, average monthly expenditure was 1809 Naira ($15.1), whilst for inpatient services it was 610 Naira ($5.1). Higher health expenditures were incurred by urban residents and the better-off SES groups. Overall, 27% of households incurred CHE, higher for poorer socioeconomic groups and for rural residents. Only 1.0% of households had a member that was enrolled in a health insurance scheme. The worse-off households (the poorest SES and rural dwellers) experienced the highest burden of health expenditure. There was almost a complete lack of financial risk protection. Health reform mechanisms are needed to ensure universal coverage with financial risk protection mechanisms.


IL-33 Upregulates Cysteinyl Leukotriene Receptor Type 1 Expression in Human Peripheral Blood CD4+ T Lymphocytes.
IL-33 and cysteinyl leukotrienes (cysLTs) are key components of asthma pathogenesis, and both contribute to the initiation and maintenance of the type 2 inflammatory environment. However, little is known about the potential interactions between the two mediators. In this work, we aimed at studying the regulation of expression of the cysLT receptors CysLT1 and CysLT2 by IL-33 in human PBLs. Our results show that the IL-33/ST2L axis increases CysLT1 but not CysLT2 expression in a concentration- and time-dependent manner in PBLs. IL-33-induced CysLT1 upregulation was observed at the protein but not at the mRNA level and was accompanied by an increase in LTD4-induced calcium mobilization and migration of CD4+ T lymphocytes. We also show that purified naive CD4+ T lymphocytes expressed ST2L and responded to IL-33 in the absence of Ag or TCR stimulation, suggesting a mechanism independent of Ag presentation. These results contribute to expanding our knowledge in the field of IL-33 by proposing a new mode of action of the cytokine on T cells and by extending its role to the regulation of naive T cell trafficking, therefore reinforcing its interest as a potential therapeutic target for the treatment of asthma.


The Jumonji C domain-containing protein JMJ30 regulates period length in the Arabidopsis circadian clock.
Histone methylation plays an essential role in regulating chromatin structure and gene expression. Jumonji C (JmjC) domain-containing proteins are generally known as histone demethylases. Circadian clocks regulate a large number of biological processes, and recent studies suggest that chromatin remodeling has evolved as an important mechanism for regulating both plant and mammalian circadian systems. Here, we analyzed a subgroup of JmjC domain-containing proteins and identified Arabidopsis (Arabidopsis thaliana) JMJ30 as a novel clock component involved in controlling the circadian period. Analysis of loss- and gain-of-function mutants of JMJ30 indicates that this evening-expressed gene is a genetic regulator of period length in the Arabidopsis circadian clock. Furthermore, two key components of the central oscillator of plants, transcription factors CIRCADIAN CLOCK ASSOCIATED1 and LATE ELONGATED HYPOCOTYL, bind directly to the JMJ30 promoter to repress its expression, suggesting that JMJ30 regulates the pace of the circadian clock in close association with the central oscillator. JMJ30 represents, to our knowledge, the first JmjC domain-containing protein involved in circadian function, and we envision that this provides a possible molecular connection between chromatin remodeling and the circadian clock.


Effects of incubation at physiological temperatures on the concentration-dependence of [2-14C]malonyl-CoA binding to rat liver mitochondria.
Specific binding of [2-14C] malonyl-CoA to rat liver mitochondria was measured at different temperatures and after various periods of time of exposure of the mitochondria to the ligand. Incubation of mitochondria at 37 degrees C in the absence of malonyl-CoA resulted in a decrease in their ability to bind malonyl-CoA at all concentrations tested (up to 55 microM). However, incubation of mitochondria in the presence of malonyl-CoA resulted in the loss of the binding only by a low-affinity component. By contrast, there was an increase in the binding that occurred at low, physiological, concentrations of malonyl-CoA. These differences in the response of the two binding components to incubation conditions were used to obtain quantitative data about their respective saturation kinetics. Evidence was obtained that, whereas the high-affinity component approached saturation hyperbolically with respect to malonyl-CoA concentration, the low-affinity component had sigmoidal characteristics. The concentrations of malonyl-CoA required to half-saturate the two components were 2-3 microM and 30 microM for the high- and low-affinity components respectively. Evidence was also obtained for the involvement of a temperature-dependent transition, that occurred at around 25 degrees C, in the modulation of malonyl-CoA binding to the mitochondria. The possible physiological roles of the two components of malonyl-CoA binding in relation to the regulation of overt carnitine palmitoyltransferase (CPT I) activity in vivo are discussed.


Facilitation of inferior frontal cortex by transcranial direct current stimulation induces perceptual learning of severely degraded speech.
Perceptual learning requires the generalization of categorical perceptual sensitivity from trained to untrained items. For degraded speech, perceptual learning modulates activation in a left-lateralized network, including inferior frontal gyrus (IFG) and inferior parietal cortex (IPC). Here we demonstrate that facilitatory anodal transcranial direct current stimulation (tDCS(anodal)) can induce perceptual learning in healthy humans. In a sham-controlled, parallel design study, 36 volunteers were allocated to the three following intervention groups: tDCS(anodal) over left IFG, IPC, or sham. Participants decided on the match between an acoustically degraded and an undegraded written word by forced same-different choice. Acoustic degradation varied in four noise-vocoding levels (2, 3, 4, and 6 bands). Participants were trained to discriminate between minimal (/Tisch/-FISCH) and identical word pairs (/Tisch/-TISCH) over a period of 3 d, and tDCS(anodal) was applied during the first 20 min of training. Perceptual sensitivity (d') for trained word pairs, and an equal number of untrained word pairs, was tested before and after training. Increases in d' indicate perceptual learning for untrained word pairs, and a combination of item-specific and perceptual learning for trained word pairs. Most notably for the lowest intelligibility level, perceptual learning occurred only when tDCS(anodal) was applied over left IFG. For trained pairs, improved d' was seen on all intelligibility levels regardless of tDCS intervention. Over left IPC, tDCS(anodal) did not modulate learning but instead introduced a response bias during training. Volunteers were more likely to respond "same," potentially indicating enhanced perceptual fusion of degraded auditory with undegraded written input. Our results supply first evidence that neural facilitation of higher-order language areas can induce perceptual learning of severely degraded speech.


Anxiolytic activity of steroid anesthetic alphaxalone.
The synthetic steroid anesthetic alphaxalone (3 alpha-hydroxy-5 alpha-pregnane-11,20-dione) was studied in two behavioral paradigms known to be sensitive to anxiolytic drugs. In an elevated plus maze, alphaxalone produced an anxiolytic profile, significantly increasing the percentage of entries made into the open arms as well as the percentage of time spent on the open arms. In the conflict test, alphaxalone (6 and 8 mg/kg) produced a significant dose-dependent increase in punished responding and a decrease (8 mg/kg) in unpunished responding. The pattern of responding was similar to that observed with the benzodiazepine agonist chlordiazepoxide (2-8 mg/kg). The increase in punished responding was not altered by the benzodiazepine antagonist Ro 15-1788 and only partially blocked by the picrotoxinin receptor ligand isopropylbicyclophospate (10 and 15 micrograms/kg). The gamma-aminobutyric acid agonists picrotoxin (1 mg/kg) and bicuculline (1 mg/kg) also failed to suppress the rate-increasing effects of alphaxalone in the conflict test. Chronic administration of alphaxalone for 1 week produced no tolerance to the anxiolytic behavioral effects. In addition, no changes in pain threshold were noted with alphaxalone (8 mg/kg) in the tail-flick analgesia test. These results suggest that the pharmacologic substrates for the anxiolytic actions of alphaxalone may be independent of either the benzodiazepine or picrotoxinin binding sites of the gamma-aminobutyric acid/benzodiazepine receptor complex.


Chronic Bronchitis Is Associated With Worse Symptoms and Quality of Life Than Chronic Airflow Obstruction.
COPD includes the chronic bronchitis (CB) and emphysema phenotypes. Although it is generally assumed that emphysema or chronic airflow obstruction (CAO) is associated with worse quality of life (QOL) than is CB, this assumption has not been tested. The current study's analyses from the Lovelace Smokers' Cohort (LSC) were validated in the COPD Gene Cohort (COPDGene). CB without CAO (CB only) was defined as self-reported cough productive of phlegm for ≥ 3 mo/y for 2 consecutive years and postbronchodilator FEV1/FVC ≥ 70%. CAO without CB (CAO only) was defined as a postbronchodilator FEV1/FVC < 70% with no evidence of CB. QOL outcomes were obtained from the St. George's Respiratory Questionnaire (SGRQ) and the 36-Item Short Form Health Survey (SF-36) questionnaires. A priori covariates included age, sex, pack-years of smoking, current smoking, and FEV1. Smokers with CB without CAO (LSC = 341; COPDGene = 523) were younger and had a greater BMI and less smoking exposure than did those with CAO only (LSC = 302; COPDGene = 2,208). Compared with the latter group, QOL scores were worse for those with CB only. Despite similar SGRQ Activity and SF-36 Role Physical and Physical Functioning, SGRQ Symptoms and Impact scores and SF-36 emotional and social measures were worse in the CB-only group, in both cohorts. After adjustment for covariates, the CB-only group remained a significant predictor for "worse" symptoms and emotional and social measures. To our knowledge, this analysis is the first to suggest that among subjects with COPD, those with CB only present worse QOL symptoms and mental well-being than do those with CAO only.


Isolation and characterization of broadly neutralizing human monoclonal antibodies to the e1 glycoprotein of hepatitis C virus.
The relative importance of humoral and cellular immunity in the prevention or clearance of hepatitis C virus (HCV) infection is poorly understood. However, there is considerable evidence that neutralizing antibodies are involved in disease control. Here we describe the detailed analysis of human monoclonal antibodies (MAbs) directed against HCV glycoprotein E1, which may have the potential to control HCV infection. We have identified two MAbs that can strongly neutralize HCV-pseudotyped particles (HCVpp) bearing the envelope glycoproteins of genotypes 1a, 1b, 4a, 5a, and 6a and less strongly neutralize HCVpp bearing the envelope glycoproteins of genotype 2a. Genotype 3a was not neutralized. The epitopes for both MAbs were mapped to the region encompassing amino acids 313 to 327. In addition, robust neutralization was also observed against cell culture-adapted viruses of genotypes 1a and 2a. Results from this study suggest that these MAbs may have the potential to prevent HCV infection.


Mangiferin attenuates MPTP induced dopaminergic neurodegeneration and improves motor impairment, redox balance and Bcl-2/Bax expression in experimental Parkinson's disease mice.
Mangiferin, a polyphenol compound of C-glucoside, is well-known for its anti-inflammatory, antioxidant, anticancer, antidiabetic and cognitive enhancement properties. In this study, we investigated the neuroprotective effect of mangiferin against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease (PD), which is most popular and widely used to evaluate therapeutic implications of new protective agents. Male C57BL/6 mice were orally treated with mangiferin (10, 20 and 40 mg/kg body wt.) for 14 days and from 10th day onwards MPTP (30 mg/kg, i.p.) was injected for last 5 days. MPTP treatment leads to enhanced oxidative stress, induction of apoptosis (upregulates the expression of Bax, proapoptotic protein and downregulates the expression of anti-apoptotic marker Bcl-2), and loss of dopominergic neurons which results in motor impairments. Results of our study confirmed that mangiferin prevented MPTP-induced behavioral deficits, oxidative stress, apoptosis, dopaminergic neuronal degeneration and dopamine depletion. Taken together, we conclude that mangiferin attenuates the dopaminergic neurodegeneration mainly through its potent antioxidant and antiapoptotic properties.


Intraoperative Detection of Persistent Endoleak by Detecting Residual Spontaneous Echocardiographic Contrast in the Aneurysmal Sac During Thoracic Endovascular Aortic Repair.
Persistent endoleaks may lead to adverse events after endovascular aortic repair. We prospectively examined the relationship between intraoperative residual spontaneous echocardiographic contrast (SEC) within the aneurysmal sac and the incidence of postoperative endoleaks in 60 patients undergoing thoracic endovascular aortic repair. Patients with SEC had a higher incidence of postoperative endoleaks than did patients without SEC within a few days postoperatively (60.0% vs 12.5%, respectively; P < .001) and at 6 months postoperatively (40.0% vs 2.5%, respectively; P < .001). Intraoperative confirmation of the absence of SEC may identify patients at low risk for persistent endoleaks after thoracic endovascular aortic repair.


Human exposure to silver released from silver-modified activated carbon applied in the new type of jug filter systems.
A water filtered by jug filter system (JFS) can be applied for the preparation of food products, as well as it can be directly consumed as drinking water. In the European Union, in both above-mentioned cases the quality of water filtered using JFSs has to fulfill the requirements listed in Directive 98/83/EC. However, Directive 98/83/EC sets no parametric value for silver, JFSs are not regulated under this legislative act and additionally, silver-modified activated carbon (applied in such systems) has not been approved by European Food Safety Authority (EFSA). Therefore, the exposure to this metal should be assessed for all JFSs containing filtration cartridges with silver-modified activated carbon, present on the retail market. A comprehensive study was conducted in order to examine the effect ofJFSs (consisted of filtration oval-cartridges of the new type with silver-modified activated carbon) on the quality of filtered water regarding the released amounts of silver. Silver migration from such type of cartridges has not been examined before. The aim of work was the assessment of exposure to silver released into filtered water from silver-modified activated carbon applied in such types of FSs. Silver migration from six brands of JFSs (A-F) was investigated according to British Standard BS 8427:2004 using a validated inductively coupled plasma mass spectrometry method. . The average daily silver concentrations in the composite samples collected on six measurement days forA, B, C, D, E and F JFSs were in the ranges of: 3.95-18.1 microg/l, 4.6-21.7 microg/l, 0.41-8.7 microLg/l, 6.9-10.9 microg/l, 3.3-17.1 microg/1 and 10.1-20.8 pg/1l, respectively. The established grand mean concentrations of released silver from all six oval cartridges were in the range of 2.7-14.3 jg/1. The estimated Hazard Quotient (HQ) indices were in the range of 0.015-0.082 CONCLUSIONS:. The estimated HQ indices were significantly lower than 1 and therefore no long-term risk for human health could be expected. All the investigated JFSs of the new type meet previously established provisional migration limit for silver from such systems--25 microg/L.


Plasma from patients with severe invasive group A streptococcal infections treated with normal polyspecific IgG inhibits streptococcal superantigen-induced T cell proliferation and cytokine production.
Previous studies have suggested a central role for superantigen-induced immune responses in the pathogenesis of streptococcal toxic shock syndrome. The production of streptococcal superantigens by clinical group A streptococcal (GAS) isolates was studied, and the ability of plasma collected from patients with severe invasive GAS infections to neutralize the proliferative- and cytokine-inducing activities of these superantigens was investigated. Overnight culture supernatants from all GAS isolates obtained from patients with invasive disease were found to contain superantigenic activity, as evident from their ability to drive potent T cell proliferation, induce high production of cytokines, and stimulate T cells in a V beta-specific manner. Twelve patients with severe invasive GAS infections, including 11 streptococcal toxic shock syndrome cases and one necrotizing fasciitis without shock, were treated with i.v. infusions of normal polyspecific Ig (IVIG). Plasma samples collected from each patient before and after IVIG administration were analyzed for their ability to neutralize the activity of streptococcal superantigens produced by the GAS isolate that caused their disease. In all IVIG-treated patients, the capacity to neutralize the superantigenic activity, produced by their respective GAS isolate or by purified streptococcal pyrogenic exotoxins, increased in plasma following IVIG administration. Of particular clinical relevance, post-IVIG plasma from each patient completely blocked cytokine production elicited by their respective GAS culture supernatants or by purified streptococcal pyrogenic exotoxins. This study shows that IVIG treatment confers in vivo inhibitory activity against a large array of streptococcal superantigens and suggests that IVIG may be useful in the treatment of severe invasive streptococcal infections.


HISTOCHEMICAL STUDIES OF LYSOSOMES AND LYSOSOMAL ENZYMES IN VIRUS-INFECTED CELL CULTURES.
The appearance of lysosomes and the distribution of lysosomal enzymes have been studied in a number of cell cultures exposed to viruses. Lysosomes were shown by fluorescence microscopy after vital staining with aminoacridines and light microscopy after vital staining with neutral red. The lysosomal enzymes studied histochemically in unfixed and fixed cells were acid phosphatase and 5-bromo-4-chloro-indoxyl acetate esterase. Activation of lysosomal enzymes was found to take place in three stages. The first is characterized by permeability of lysosomal membranes without release of enzymes. This is demonstrable by staining of lysosomal enzymes in unfixed cells and by increased uptake of aminoacridine fluorochromes and neutral red into lysosomes. In cell sheets initially stained with neutral red this gives rise to red plaques. This stage can be fully reversible; cells infected with, and yielding, the red-plaque strain of NDV, recover fully afterwards. In the second stage lysosomal enzymes are released into the cytoplasm, the cells round up and there is decreased uptake of aminoacridines and neutral red into lysosomes. In cell monolayers this results in the formation of white plaques. In the third stage, not usually seen in cell cultures, lysosomal enzymes are released from or inactivated in the cells and are not seen in either fixed or unfixed preparations. The possible roles of lysosomal enzymes in production of cytopathic effects, polykaryocytosis and malignant cell transformation are discussed.


Physical exercise and psychological well being: a critical review.
The relation between physical exercise and psychological health has increasingly come under the spotlight over recent years. While the message emanating from physiological research has extolled the general advantages of exercise in terms of physical health, the equivalent psychological literature has revealed a more complex relation. The paper outlines the research evidence, focusing on the relation between physical exercise and depression, anxiety, stress responsivity, mood state, self esteem, premenstrual syndrome, and body image. Consideration is also given to the phenomena of exercise addiction and withdrawal, and implications for exercise prescription are discussed.


Incentivizing Commuter Cycling by Financial and Non-Financial Rewards.
Current mobility patterns over-rely on transport modes that do not benefit sustainable and healthy lifestyles. To explore the potential for active mobility, we conducted a randomized experiment aimed at increasing regular commuter cycling in cities. In designing the experiment, we teamed up with developers of the "Cyclers" smartphone app to improve the effectiveness of the app by evaluating financial and non-financial motivational features. Participants in the experiment were recruited among new users of the app, and were randomly assigned to one of four different motivational treatments (smart gamification, two variants of a financial reward, and a combination of smart gamification and a financial reward) or a control group (no specific motivation). Our analysis suggests that people can be effectively motivated to engage in more frequent commuter cycling with incentives via a smartphone app. Offering small financial rewards seems to be more effective than smart gamification. A combination of both motivational treatments-smart gamification and financial rewards-may work the same or slightly better than financial rewards alone. We demonstrate that small financial rewards embedded in smartphone apps such as "Cyclers" can be effective in nudging people to commute by bike more often.


Study protocol for a randomized controlled trial of the RASPERA project: recalling and anticipating specific positive events to boost resilience in adolescents.
Many stress-related mental health problems, like depression and anxiety, emerge during adolescence, with some recent studies suggesting numbers are increasing. One possible way to reduce adolescents' vulnerability to stress-related mental health problems is to increase their resilience by training them in recalling specific positive memories and anticipating specific positive future events. Therefore, an innovative combi-training (called Positive Events Training; PET) was developed, focusing on the enhancement of the specificity of both past and future positive autobiographical events in adolescents. Its effects on adolescents' resilience and mental wellbeing will be examined. A cluster randomized controlled trial with a 2 (condition) × 3 (time-point) factorial design was conducted. Classes of adolescents were randomized to either a PET program (intervention) or a CREAtive writing Training (CREAT) program (active control). Both trainings consisted of four sessions of 50 min (one session, weekly, for four consecutive weeks) and were delivered in schools. Before (pre-training, T1), immediately after (post-training, T2), and 2 months after the training (follow-up, T3), participants completed a series of self-report questionnaires. Primary outcomes are resilience and mental wellbeing. Secondary outcomes are positive affect, positive affect regulation and anhedonia. CONSORT criteria for conducting and reporting RCTs will be used. Ethical approval was obtained from the Social and Societal Ethics Committee (SMEC) and the study has been preregistered on Open Science Framework (OSF) and ClinicalTrials.gov (Trial registration number: NCT05757180). We plan to develop a free, online, web-based self-directed PET protocol for teachers if the study provides evidence for the effectiveness of the PET program in increasing adolescents' resilience and mental wellbeing, so teachers can deliver the program to future students without the need of professional external trainers.


Oral manifestations of recently described viral infections, including AIDS.
Oral viral diseases secondary to human immunodeficiency virus-1 infection are not commonly observed, except for Epstein-Barr virus infection. For the most part, members of the herpes virus group and the human papilloma viruses are involved. With the introduction of techniques like the polymerase chain reaction, the level of detection has been changed considerably. However, the application of these techniques may also result in difficulties of interpretation, such as is the case with the detection of human papilloma virus in human immunodeficiency virus-associated Kaposi's sarcoma, as recently described. The possible association of "new" viruses with well-known diseases such as Sjögren's syndrome or Paget's disease are of great interest; but the etiologic role of these particles in the disease process has yet to be determined (Scully, in Millard and Mason, eds. Perspectives on 1988 World Workshop on Oral Medicine. YearBook Publishing, 1989, pp 179-182). Oral manifestations in the course of human immunodeficiency virus disease and acquired immunodeficiency syndrome are numerous and have long been considered important for clinical diagnostic reasons. The present review is focused on viral diseases with oral manifestations associated with human immunodeficiency virus infection as well as with some "new" viral diseases that may also produce orofacial symptoms.


Treatment of bias in estimating measurement uncertainty.
Bias in an analytical measurement should be estimated and corrected for, but this is not always done. As an alternative to correction, there are a number of methods that increase the expanded uncertainty to take account of bias. All sensible combinations of correcting or enlarging uncertainty for bias, whether considered significant or not, were modeled by a Latin hypercube simulation of 125,000 iterations for a range of bias values. The fraction of results for which the result and its expanded uncertainty contained the true value of a simulated test measure and was used to assess the different methods. The strategy of estimating the bias and always correcting is consistently the best throughout the range of biases. For expansion of the uncertainty when the bias is considered significant is best done by SUMU(Max):U(C(test result))=ku(c)(C(test result))+ |delta(run)|, where k is the coverage factor (= 2 for 95% confidence interval), u(c) is the combined standard uncertainty of the measurement and delta(run) is the run bias.


The effectiveness of hyperbaric oxygen therapy for healing chronic venous leg ulcers: A randomized, double-blind, placebo-controlled trial.
Over 30% of venous leg ulcers do not heal despite evidence-based treatment. This study aimed to determine the effectiveness of Hyperbaric Oxygen Therapy (HBOT) as an adjunct treatment for nonhealing venous leg ulcers. A randomized, double-blind, parallel group, placebo-controlled trial was undertaken in three hyperbaric medicine units. Adults with a venous leg ulcer, Transcutaneous Oxygen Measurement indicative of a hypoxic wound responsive to oxygen challenge, and without contraindications for HBOT; were eligible. Of 84 eligible patients, 10 refused and 74 enrolled. 43 participants achieved over 50% ulcer Percent Area Reduction (PAR) after four weeks of evidence-based care and were thus excluded from the intervention phase. Thirty-one participants were randomized to either 30 HBOT treatments (100% oxygen at 2.4 atmospheres absolute (ATA) for 80 minutes), or 30 "placebo" treatments, receiving a validated "sham" air protocol, initially pressurized to 1.2ATA, then cycled between 1.05-1.2ATA for eight minutes before settling at 1.05ATA. The primary outcome was numbers in each group completely healed. Secondary outcomes were ulcer PAR, pain and quality of life, 12 weeks after commencing interventions. The participants' mean age was 70 years (standard deviation (SD) 12.9) and median ulcer duration at enrolment was 62 weeks (range 4-3120). At 12 weeks, there was no significant difference between groups in the numbers completely healed. The HBOT intervention group had a mean of 95 (SD 6.53) ulcer PAR, compared to 54 (SD 67.8) mean PAR for the placebo group (t = -2.24, p = 0.042, mean difference -40.8, SE 18.2) at 12 weeks. HBOT may improve refractory healing in venous leg ulcers, however patient selection is important. In this study, HBOT as an adjunct treatment for nonhealing patients returned indolent ulcers to a healing trajectory.


Changes in sleep duration associated with retirement transitions: The role of naps.
This study examined the changes in sleep duration (total sleep time, night-time sleep and daytime naps) after retirement transitions in China using a panel dataset of the China Health and Retirement Longitudinal Study in 2011, 2013 and 2015 with a total of 48,458 respondents. Linear regression analysis with generalized estimating equations was employed to examine the changes in sleep duration after transitions between different types of employment status. After controlling for the confounders, the results showed that the retired population and the population working in agricultural sectors slept 8.02 (p < .01) and 5.19 (p < .01) minutes longer than the population working in non-agricultural sectors, respectively. Employment transition also had significant effects on sleep duration. Transition from non-agricultural sectors to retirement increased total sleep time by 13.58 (p < .01) minutes and also raised the probability of daytime naps by 18% (OR = 1.18, p < .01). Transition from agricultural employment to retirement did not significantly affect the total sleep time, but significantly increased the probability of daytime naps (OR = 1.12, p = .02). Reentering the non-agricultural sectors for the retirees did not significantly affect night-time sleep, but decreased the probability of daytime naps (OR = 0.73, p < .01) and daytime nap duration (by 5.26 min, p = .01). In conclusion, people in China increased their sleep duration after transitions to retirement, but the magnitudes were much smaller than those in Western countries. Differences may be attributed to an abundant amount of Chinese people working in agricultural sectors, the high volume of retired people reentering the work force and the large proportion of people in China that had daytime naps at baseline.


Aluminum intoxication in vitamin D-deficient rats: studies of bone aluminum localization and histomorphometry before and after vitamin D repletion.
Aluminum accumulation by both dialysis patients and nonuremic patients, requiring chronic total parenteral nutrition, may be an etiological factor in the development of severe osteomalacia. To study the role of aluminum toxicity in bone, further experiments have been conducted in the nonuremic, vitamin D-deficient rat. Weanling rats were raised on vitamin D-deficient diets, and half received parenteral aluminum (5 mg/wk), for 30 days. In the first experiment low doses of 25-OH cholecalciferol (500 ng/week) were given subcutaneously for a further 30 days. Control rats were maintained on a similar protocol, but were supplemented with cholecalciferol (5 micrograms/week) from the outset until sacrifice at 60 days. In the second experiment a single bolus of cholecalciferol (5 micrograms) was given to study short-term changes in serum biochemistry and bone histology at 96 hr. Quantitative bone histomorphometric analyses of the proximal tibial metaphysis were made in all experimental groups. In the experimental vitamin D-deficient group, with the highest bone aluminum content (as assessed by extraction of whole bone aluminum), X-ray microanalysis was performed to determine the distribution of aluminum in bone tissue and bone cell organelles. The results showed that control rats treated with prolonged aluminum therapy (30 mg over 60 days) had evidence of both reduced osteoid matrix synthesis and mineralization. However, in vitamin D-deficient rats, there was no evidence that aluminum exacerbated the osteomalacic lesion, even though there was histochemical evidence of aluminum deposition at the bone-osteoid interface.(ABSTRACT TRUNCATED AT 250 WORDS)


ID helix-loop-helix proteins as determinants of cell survival in B-cell chronic lymphocytic leukemia cells in vitro.
Members of the inhibitor of DNA-binding (ID) family of helix-loop-helix proteins have been causally implicated in the pathogenesis of several types of B-cell lineage malignancy, either on the basis of mutation or by altered expression. B-cell chronic lymphocytic leukemia encompasses a heterogeneous group of disorders and is the commonest leukaemia type in the Western world. In this study, we have investigated the pathobiological functions of the ID2 and ID3 proteins in this disease with an emphasis on their role in regulating leukemic cell death/survival. Bioinformatics analysis of microarray gene expression data was used to investigate expression of ID2/ID3 in leukemic versus normal B cells, their association with clinical course of disease and molecular sub-type and to reconstruct a gene regulatory network using the 'maximum information coefficient' (MIC) for target gene inference. In vitro cultured primary leukemia cells, either in isolation or co-cultured with accessory vascular endothelial cells, were used to investigate ID2/ID3 protein expression by western blotting and to assess the cytotoxic response of different drugs (fludarabine, chlorambucil, ethacrynic acid) by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. ID2/ID3 protein levels in primary leukemia cells and in MEC1 cells were manipulated by transduction with siRNA reagents. Datamining showed that the expression profiles of ID2 and ID3 are associated with distinct pathobiological features of disease and implicated both genes in regulating cell death/survival by targeting multiple non-overlapping sets of apoptosis effecter genes. Consistent with microarray data, the overall pattern of ID2/ID3 protein expression in relation to cell death/survival responses of primary leukemia cells was suggestive of a pro-survival function for both ID proteins. This was confirmed by siRNA knock-down experiments in MEC1 cells and in primary leukemia cells, but with variability in the dependence of leukemic cells from different patients on ID protein expression for cell survival. Vascular endothelial cells rescued leukemia cells from spontaneous and cytotoxic drug-induced cell death at least in part, via an ID protein-coupled redox-dependent mechanism. Our study provides evidence for a pro-survival function of the ID2/ID3 proteins in chronic lymphocytic leukemia cells and also highlights these proteins as potential determinants of the pathobiology of this disorder.


[Neuropsychiatric disorders in adolescent disorders of menstrual function].
The clinical time-course of the psychic status was examined in 98 girls aged 11 to 16 years who suffered from juvenile hemorrhagas. The author identified the asthenovegatative (n-30), anxiety (n-29), anxiety-hypochondriac (n-19), obsessive-fobic (n-20) and depressive-hypochondrias (n-21) syndromes. These states reflected a relatively superficial (neurotic) level of neuropsychic disorders in the patients.


Increased expression in vivo and in vitro of foreign genes directed by A-type inclusion body hybrid promoters in recombinant vaccinia viruses.
We constructed A-type inclusion body (ATI) hybrid promoters, that is, late ATI promoters followed by tandemly repeated early regions of the promoter for the 7.5-kDa protein (the 7.5-kDa promoter). The repetition of the whole early promoter sequence of the 7.5-kDa gene, including the upstream consensus sequence and initiation region, efficiently increased the early expression of the bacterial chloramphenicol acetyltransferase gene in recombinant vaccinia virus. Recombinant vaccinia virus could express influenza virus hemagglutinin via the hybrid promoter more efficiently, induced higher levels of neutralizing antibody and cytotoxic T lymphocytes, and consequently protected mice more efficiently against challenge with influenza virus than did recombinant vaccinia virus containing the widely used 7.5-kDa promoter.


Antiphospholipid syndrome: an update for clinicians and scientists.
Antiphospholipid syndrome (APS) is a leading acquired cause of thrombosis and pregnancy loss. Upon diagnosis (which is unlikely to be made until at least one morbid event has occurred), anticoagulant medications are typically prescribed in an attempt to prevent future events. This approach is not uniformly effective and does not prevent associated autoimmune and inflammatory complications. The goal of this review is to update clinicians and scientists on mechanistic and clinically relevant studies from the past 18 months, which have especially focused on inflammatory aspects of APS pathophysiology. How antiphospholipid antibodies leverage receptors and signaling pathways to activate cells is being increasingly defined. Although established mediators of disease pathogenesis (like endothelial cells and the complement system) continue to receive intensive study, emerging concepts (such as the role of neutrophils) are also receiving increasing attention. In-vivo animal studies and small clinical trials are demonstrating how repurposed medications (hydroxychloroquine, statins, and rivaroxaban) may have clinical benefit in APS, with these concepts importantly supported by mechanistic data. As anticoagulant medications are not uniformly effective and do not comprehensively target the underlying pathophysiology of APS, there is a continued need to reveal the inflammatory aspects of APS, which may be modulated by novel and repurposed therapies.


Assessing parenting risk within the context of severe and persistent mental illness: Validating an observational measure for families with child protective service involvement.
Women with severe and persistent mental illness (SMI) face formidable challenges as parents. While many raise their children to adulthood, others struggle considerably in the parenting role. In cases where there is child protective service involvement, an assessment may be requested to establish what risks an individual with SMI poses as a parent. Unfortunately, many current approaches to parenting assessments have serious methodological problems. One problem is a lack of valid and reliable measures to assess the parenting behavior of individuals with SMI who have child protective service involvement. In an effort to improve the quality of parenting assessments for this vulnerable group, this study drew on a sample of mothers with SMI who had lost custody of a child to examine the reliability and validity of the Child and Adult Relational Experimental Index (CARE-Index), an observational measure of parenting behavior. Independent and trained raters achieved a high level of reliability on the measure. Mothers' ratings on the measure also were associated with children's interactive behavior and with an estimation of risk based on a multifaceted, comprehensive assessment. The measure's relation to estimation of risk remained significant when two other predictors of risk, maternal caregiving attitudes and insight into mental illness, were considered. Taken together, the findings suggest that the measure can provide reliable, valid, and independent information on parenting behavior that could inform comprehensive, multifaceted assessments of parenting risk.


Selective internal operations in the recognition of locally and globally point-inverted patterns.
Performance in discriminating rotated 'same' patterns from 'different' patterns may decrease with rotation angle up to about 90 degrees and then increase with angle up to 180 degrees. This anomalously improved performance under 180 degrees pattern rotation or point-inversion can be explained by assuming that patterns are internally represented in terms of local features and their spatial-order relations ('left of', 'above', etc.), and that, in pattern comparison, an efficient internal sense-reversal operation occurs (transforming 'left of' to 'right of', etc.). Previous experiments suggested that local features and spatial relations could not be efficiently separated in some pattern-comparison tasks. This hypothesis was tested by measuring 'same-different' discrimination performance under four transformation: point-inversion 1 of the whole pattern, point-inversion 1F of local features alone, point-inversion 1P of local-feature positions alone, and identity transformation Id. The results suggested that internal sense-reversal operations could be applied selectively and efficiently, provided that local features were well separated. Under this condition performances for 1F and 1 were about the same whereas performance for 1P was significantly worse, the latter performance resulting possibly from an attempt to apply internal global and local sense-reversal operations serially.


Asymmetry after hamstring injury in English Premier League: issue resolved, or perhaps not?
Hamstring injuries constitute one of the most concerning injuries in English Premier League football, due to its high primary incidence but also its recurrence. Functional methods assessing hamstring function during high-risk performance tasks such as sprinting are vital to identify potential risk factors. The purpose of this study was to assess horizontal force deficits during maximum sprint running on a non-motorized treadmill in football players with previous history of hamstring strains as a pre-season risk-assessment in a club setting. 17 male football players from one Premier League Club were divided into 2 groups, experimental (n=6, age=24.5±2.3 years) and control (n=11, age=21.3±1.2 years), according to history of previous hamstring injury. Participants performed a protocol including a 10-s maximum sprint on a non-motorized treadmill. Force deficits during acceleration phase and steady state phases of the sprint were assessed between limbs and between groups. The main outcome measures were horizontal and vertical peak forces during the acceleration phase or steady state. There were no significant differences in peak forces between previously injured and non-injured limbs, or between groups, challenging the ideas around functional force deficits in sprint running as a diagnostic measure of hamstring re-injury risk.


The relationship of extent of initial radiological involvement with the need of intensive care, mortality rates, and laboratory parameters in Covid-19
It is very important for the efficient use of limited capacity and the success of treatment to predict patients who may need ICU with high mortality rate in the Covid-19 outbreak. In our study, it was aimed to investigate the value of the radiological involvement on initial CT in demonstrating the ICU transfer and mortality rate of patients. All PCR-positive patients were included in the study, whose CT, PCR, and laboratory values were obtained simultaneously at the time of first admission. Patients were divided into 4 groups in terms of the extent of radiological lesions. These groups were compared in terms of intensive care transfer needs and Covid-related mortality rates. A total of 477 patients were included in the study. Ninety of them were group 0 (no lung involvement), 162 were group 1 (mild lesion), 89 were group 2 (moderate lesion), and 136 were group 3 (severe lung involvement). A significant relationship was found between the extensiveness of the radiological lesion on CT and admission to intensive care and mortality rate. As the initial radiological involvement amounts increased, the rate of ICU transfer and mortality increased. The mortality rates of the groups were 0%, 3%, 12.3%, and 12.5%, respectively, and the difference was significant (p < 0.001). Similarly, the ICU transfer rates of the groups were 2.2%, 5.6%, 13.5%, and 17.7%, respectively, and the difference was significant (p < 0.001). In conclusion, in our study, the strong relationship between the initial radiological extent assessment and the need for intensive care and mortality rates has been demonstrated, and we believe that our results will make a significant contribution to increase the success of the health system in predicting patients who may progress, helping clinicians and managing pandemics.


Telbivudine/Torcitabine Idenix/Novartis.
Idenix (formerly Novirio) and Novartis are developing two beta-L-deoxynucleosides, telbivudine and torcitabine, for the potential treatment of hepatitis B virus infection. Phase III trials of telbivudine were underway by August 2002 and phase I/II trials of the torcitabine prodrug, valtorcitabine, were ongoing in November 2003.


Gene expression profiling of a mouse model of pancreatic islet dysmorphogenesis.
In the past decade, several transcription factors critical for pancreas organogenesis have been identified. Despite this success, many of the factors necessary for proper islet morphogenesis and function remain uncharacterized. Previous studies have shown that transgenic over-expression of the transcription factor Hnf6 specifically in the pancreatic endocrine cell lineage resulted in disruptions in islet morphogenesis, including dysfunctional endocrine cell sorting, increased individual islet size, increased number of peripheral endocrine cell types, and failure of islets to migrate away from the ductal epithelium. The mechanisms whereby maintained Hnf6 causes defects in islet morphogenesis have yet to be elucidated. We exploited the dysmorphic islets in Hnf6 transgenic animals as a tool to identify factors important for islet morphogenesis. Genome-wide microarray analysis was used to identify differences in the gene expression profiles of late gestation and early postnatal total pancreas tissue from wild type and Hnf6 transgenic animals. Here we report the identification of genes with an altered expression in Hnf6 transgenic animals and highlight factors with potential importance in islet morphogenesis. Importantly, gene products involved in cell adhesion, cell migration, ECM remodeling and proliferation were found to be altered in Hnf6 transgenic pancreata, revealing specific candidates that can now be analyzed directly for their role in these processes during islet development. This study provides a unique dataset that can act as a starting point for other investigators to explore the role of the identified genes in pancreatogenesis, islet morphogenesis and mature beta cell function.


Controversies in radioiodine therapy: relation to ophthalmopathy, the possible radioprotective effect of antithyroid drugs, and use in large goitres.
In routine use for more than 50 years, radioiodine ((131)I) is generally considered safe and devoid of major side effects. Therefore, it is surprising that relatively many aspects of radioiodine therapy are controversial, as illustrated by recent international questionnaire studies. Our review aims at highlighting three of these areas - namely, the influence of (131)I on the course of Graves' ophthalmopathy, the possible radioprotective effects of antithyroid drugs, and the use of (131)I in large goitres. (131)I therapy carries a small (but definite) risk of causing progression of Graves' ophthalmopathy. Identification of risk factors (thyroid dysfunction, high level of thyroid-stimulating hormone (TSH) receptor antibodies, cigarette smoking) allows the identification of patients at risk and the institution of concomitant glucocorticoid treatment, thereby hindering progression of eye disease. On the basis, largely, of retrospective data, it appears that carbimazole (or methimazole), if stopped 3-5 days before treatment, does not influence the outcome of (131)I therapy. Simultaneous thyrostatic medication most probably reduces the efficacy of (131)I, as does restarting it within 7 days. Propylthiouracil seems to have a more prolonged radioprotective effect than carbimazole. Surgery is the treatment of first choice in patients with a large goitre. However, in the case of patient ineligibility or preference, (131)I therapy may be an option. The treatment has a favourable effect on tracheal compression and inspiratory capacity, but the reduction in thyroid volume is only 30-40%. Inpatient treatment, necessitated by the large doses, makes the treatment cumbersome. Controversy related to radioiodine therapy is mainly based on the lack of adequate prospective randomised studies comparing efficacy, side effects, cost and patient satisfaction.


Controversies and evidence for cardiovascular disease in the diverse Hispanic population.
Hispanics account for approximately 17% of the U.S. They are one of the fastest growing racial/ethnic groups, second only to Asians. This heterogeneous population has diverse socioeconomic conditions, making the prevention, diagnosis, and management of vascular disease difficult. This paper discusses the cultural, racial, and social aspects of the Hispanic community in the United States and assesses how they affect vascular disease within this population. Furthermore, it explores risk factors, medical and surgical treatments, and outcomes of vascular disease in the Hispanic population; generational evolution of these conditions; and the phenomenon called the Hispanic paradox. A systematic search of the literature was performed to identify all English-language publications from 1991 to 2014 using PubMed, which draws from the National Institutes of Health and U.S. National Library of Medicine, with the words "cardiovascular disease," "prevalence," "vascular," and "Hispanic." An additional search was performed using "cardiovascular disease and Mexico," "cardiovascular disease and Cuba," "cardiovascular disease and Puerto Rico," and "cardiovascular disease and Latin America" as well as for complications, management, outcomes, surgery, vascular disease, and Hispanic paradox. The resulting publications were queried for generational data (spanning multiple well-defined age groups) regarding cardiovascular disease, and cross-references were obtained from their bibliographies. Results are segmented by country of origin. Compared with non-Hispanic whites, Hispanics face higher risks of cardiovascular diseases because of a high prevalence of high blood pressure, obesity, diabetes mellitus, and ischemic stroke. However, the incidence of peripheral arterial disease and carotid disease appears to be significantly lower than in whites. The Hispanic paradox (lower mortality in spite of higher cardiovascular risk factors) may relate to challenges in ascribing life expectancy and cause of death in this diverse population. Low socioeconomic status and high prevalence of concomitant diseases negatively influence the outcomes of all patients, independent of being Hispanic. Understanding the cultural diversity in Hispanics is important in terms of targeting preventive measures to modify cardiovascular risk factors, which affect development and outcomes of vascular disease. The available literature regarding vascular disease in the Hispanic population is limited, and further longitudinal study is warranted to improve health care delivery and outcomes in this group.


[Radioprotective effect of "light" water: doubtful validity].
Several publications have reported a radioprotective and immunopotentiating action of "light" water with low content of such stable isotopes as deuterium and 18O. Validity of these statements is the subject of the Letter to editors. Investigations of "light" water compare with that of water purified of a microelement. Prolonged consumption of this water may result in deficiency of the microelement, whereas the positive effect of absence in water of a natural microcomponent is impossible or very unlikely.


RIC-8 is required for GPR-1/2-dependent Galpha function during asymmetric division of C. elegans embryos.
Heterotrimeric G proteins are crucial for asymmetric cell division, but the mechanisms of signal activation remain poorly understood. Here, we establish that the evolutionarily conserved protein RIC-8 is required for proper asymmetric division of one-cell stage C. elegans embryos. Spindle severing experiments demonstrate that RIC-8 is required for generation of substantial pulling forces on astral microtubules. RIC-8 physically interacts with GOA-1 and GPA-16, two Galpha subunits that act in a partially redundant manner in one-cell stage embryos. RIC-8 preferentially binds to GDP bound GOA-1 and is a guanine nucleotide exchange factor (GEF) for GOA-1. Our analysis suggests that RIC-8 acts before the GoLoco protein GPR-1/2 in the sequence of events leading to Galpha activation. Furthermore, coimmunoprecipitation and in vivo epistasis demonstrate that inactivation of the Gbeta subunit GPB-1 alleviates the need for RIC-8 in one-cell stage embryos. Our findings suggest a mechanism in which RIC-8 favors generation of Galpha free from Gbetagamma and enables GPR-1/2 to mediate asymmetric cell division.


Facial verruca plana that developed after semipermanent tattooing.
Tattooing is becoming more popular around the world. As a result, the reported complications of tattoo are increasing. Local inflammation, infection and allergic reactions are the most common adverse effects. We report here on a healthy 39-year-old woman who developed multiple verruca plana lesions after undergoing semipermanent tattooing. The tattooing had been done 1 year earlier by an amateur.